On Sunday, November 6, Lorenz Studer, MD, director of the Sloan Kettering Institute (SKI) for Stem Cell Biology, published a paper in the journal Nature on a new strategy for using embryonic stem (ES) cells to graft human dopamine neurons into pre-clinical models of Parkinson's disease (PD). Historically, ES cells have shown promise for treating PD in a Petri dish, they have not yet been effective once transplanted into a living organism. Dr. Studer's new technique, however, has revealed new promise in models of PD, reflecting the potential for dopamine cells' survival and function in the brain. Dr. Studer was funded by The Michael J. Fox Foundation (MJFF) in 2001 to investigate the potential of ES cells to treat PD, and was part of the team that first successfully induced human ES cells to turn into dopamine neurons in research experiments. We spoke with Dr. Studer and with Brian Fiske, PhD, the Foundation's director of research programs, to gauge the impact of this recent discovery, and to discuss why the process of developing stem cell therapies is such a long and arduous one. While Dr. Studer's results are promising, there is still much work to be done before stem cells can be considered a viable therapeutic option for PD.

MJFF: Dr. Fiske, what is cell replacement therapy and how may it one day help people with PD?

BF: Cell replacement therapy seeks to restore function in the body by replacing cells lost due to disease with new, healthy ones. In PD, this means replacing dopamine cells in the brain, the main type of cell that degenerates in the disease. Researchers hope that one day they will be able to use stem cells to successfully engineer healthy new dopamine-producing cells. These healthy cells would then be implanted into the brain, where the cells could in theory restart the brain's production of dopamine and restore normal movement.

MJFF: Historically, what challenges have stood in the way of making this happen?

BF: Scientists are working on two major challenges: first, engineering the dopamine-producing cells, and second, getting these cells to function properly once they are transplanted into the brain. To date, they have had the most success generating robust dopamine neurons, in both quantity and quality, using ES cells. However, whether these engineered dopamine neurons are sufficiently 'authentic' -- that is, whether they express everything natural ones do -- is a remaining challenge.

Even if seemingly authentic dopamine neurons can be generated, researchers face an enormous hurdle in coaxing these cells to grow and make the correct connections in a host brain. This involves determining where to place the cell grafts and how to deliver them without causing additional brain damage or triggering immune rejection or inflammatory effects.

Additionally, the new cells must also be able to retain the characteristics of a dopamine neuron once implanted in the brain, where they will be exposed to other factors that may influence their further development and survival. In research to date, engineered cells have not survived for long following implantation. They have often turned into different cell types -- in some cases, they have caused uncontrolled cell growth. Dr. Studer's paper, however, suggests that his team has created cells that both survive over the long-term in pre-clinical models, and do not proliferate at an uncontrollable rate. This could have major implications for the use of stem cells in PD therapeutics.

MJFF: Dr. Studer, tell us more about your study's findings.

LS: After many years of trying, we have finally created a method to use human stem cells to generate dopamine nerve cells that maintain their function in pre-clinical models of PD. As Dr. Fiske previously explained, in the past, we were able to make cells in a Petri dish that took on many of the features of dopamine nerve cells. But when these cells were transplanted into pre-clinical models, they either died very quickly, or the cells that did survive tended to overgrow. It was such a mystery: Why did these cells look so good in a Petri dish, but not in a whole organism?

Another point of contention has surrounded why the cells didn't take the way we wanted them to: Was it because of the environment in which we were placing the cells, or was it the cells themselves? We have figured this out -- it was the cells themselves, and we have created a new recipe for making them.

Historically, two specific cell pathways were used to make these cells. By delving back into the developmental biology, we figured out that a third pathway was missing from the equation. So we used a small molecule compound, which is a little bit like a pharmaceutical drug, to trigger this third pathway. By doing this, dopamine growth was activated, and at a much higher level of efficiency than we had previously seen. But more important than that, when we injected these cells into pre-clinical models of PD, they survived very well and were functionally active, meaning that the movement deficits in these models were largely corrected. In fact, after four or five months, several movement deficits were completely restored.

MJFF: How are you following up on this discovery in your current work?

LS: Another exciting aspect of this study was that we were able to show that our new technique can quite easily be scaled up in size. While it's not yet ready for study in humans, we were able to transplant these cells into a larger size pre-clinical model, and we found that they took to the brain very well, while showing the exact same characteristics as in the smaller models. We haven't yet done long-term functional studies in these larger models, so that is next, as we aim to determine if we can restore more complex movements.

We are also working with a specialized Good Manufacturing Practices facility to produce a very large number of cells. Over the next few years, we will test these cells in pre-clinical models to determine their efficacy and safety at a greater scale. This will help us to optimize procedures surrounding the production and purification of our cells ahead of a potential clinical study.

MJFF: What might this new study mean for cell replacement therapy moving forward?

LS: There are still many hurdles to overcome. In addition to showing that these cells work really well in large pre-clinical models over the long-term, we need to address the potential side effects of cell replacement therapy in human beings. This is a major concern -- in past studies on PD, grafted cells did survive in human brains. However, in one such study using fetal cell transplants, the graft made the subjects' dyskinesia significantly worse than before the trial. Eventually, we will test our cells in a specific dyskinesia-prone model of PD, and hopefully this will prove to reduce dyskinesias, and not worsen them.

Again, we have a long way to go -- stringent clinical studies would have to follow our studies in pre-clinical models. But we are optimistic.

MJFF: Realistically, what kind of timeline are we looking at before your technique makes its way to the clinic?

LS: People always ask how long it will take before cell replacement therapy is a viable option, and we've never had a good answer. But we've also never had a really good way to make the correct cell. Now we believe we do. The question now is more one of engineering than biology, so I think a timeline is more predictable. The big question is, can we better influence the behavior of the cells once we transplant them. Right now, we kind of place them in a black box and hope for the best. We're still perfecting how to better control the cells once they're transplanted into the brain.

Certainly, a lot can still go wrong. But if everything goes right, we believe we could establish these large-scale banks within three to four years. After that, we could begin to start thinking about clinical trials. We have set up a multidisciplinary team here at SKI and several neighboring institutions in New York comprising neurologists, neurosurgeons, and cell engineers to begin to think about the steps we will need to take to move into the clinic. We are confident that this group can go a long way to help us to make the right decisions moving forward.

NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.